Muscle relaxant and tranquilizer composition and method employing 4,5-dimethyl - 5 - ethyl - 4 - hydroxy - 3 - hydroxy-ethyl-1,3-oxazolidin-2-one



United States Patent "i e 3,542,926

Patented Nov. 24, 1970 3 542 9 of the compound of interest to thepresent invention from MUSCLE RELAXANT AN1) TRANQUILIZER COM- commStartmg mammals- POSITION AND METHOD EMPLOYING 4,5-DI- EXAMPLE 1 METHYLETHYL 4 HYDROXY 3 HY- DROXY ETHYL 1,3 0XAZ0L]D1N 2 0NE 5 Preparation of4,5-dimethyl-5-ethyl-4-hydroxy-3-hy- Julius George Shukys, Chatham,N.J., assignor to Air Redfoxyethyl'L3-OXEIZQhdm-Z-OHB duction Company,Incorporated, New York, N.Y., a

corporation of New York To 4 methyleneS-methyl-S-ethyl-l,3-dioxolan-2-one No Drawing. Filed Oct. 25, 1968,Ser. No. 770,824 (71 mole) was added Slowly to a Solution of CL A61k27/00 ethanolamlne (30.6 g., 0.5 mole) and 190 ml. benzene. US, Cl.424-272 2 Cl i The reaction mixture was agitated and the temperature wasmaintained at 40 C. by means of a cold water bath. After the addition ofthe amino alcohol and when the ABSTRACT OF THE DISCLOSURE temperaturebegan to fall, the reaction mixture was heated This invention relates tocompositions containing 4,5- to and maintained at 500 for about 4 Thesolvent i l 5 h 1-4 h -3 h d l 1 3 1i was then removed at reducedpressure (06 mm. absolute).

in-2-one and a pharmaceutically acceptable carrier for The residue,Wfiighing 100-7 had a melting Point Of use in producing musclerelaxation and a state of tran- 842900 After two clystanizatiohs frombenZeIle, the quility in warm-blooded mammals and the method ofPr0d11tme1t@dat9193 preparing and using such compositions. for C9H1'ZO4N(P 5318; H, 8.43; N, 6.89. Found (percent): (3, 53.52; H, 8.97; N, 6.82.

DESCRIPTION OF THE INVENTION Before testing any of the compositions ofthe present invention for use in producing muscle relaxation and a stateof tranquility in warm-blooded mammals the LD of the effective compoundwas determined. The LD corresponds to the amount of compound necessaryto kill 50% of the mice tested in a given period of time. The LD wasdetermined through the intraperitoneal administration of the compound to28 female OF 1S mice.

The present invention relates to compositions containing 4,5dimethyl-5-ethyl-4-hydroxy-3-hydroxyethyl-1,3- oxazolidin-Z-one whichare useful for producing muscle relaxation and a state of tranquility inwarm-blood mammals. The effective compound in the composition of thepresent invention has the following structural formula: 30

E 3 The LD was found to be over 7500 mg./kg. indicating that thecompound was extremely safe for use in testing. 0 N C2H4OH In order totest the effectiveness of the composition of the present invention inproducing muscle relaxation and a state of tranquility in warm-bloodedanimals, solutions 0 of the compounds were prepared in apharmaceutically The compound 4,5-dimethyl-5-ethyl-3-hydroxy-3-hyacceptable carrier. Since the compound of interest isdroxyethyl-1,3-oxazolidin-2-one is a white crystalline solid,Water-Soluble, Wat'er Serves as f fy is ol bl i t d h an i i l f l 40other pharmaceutically acceptable carrier, in which the C I-I O N, It ha molecular i h of 203 d a ltcompound is soluble would also be suitable,for example, ing point f91 93 C, an isotonic saline solution. Thecompositions can also The compound used in preparing the composition ofbe prepared as emulsions employing pharmaceutically the presentinvention can be prepared by reacting acceptable carriers in which thecompound is insoluble. ethanolamin ith 4-m thy1 e-5 th l-5-eth l-dioxolaThe solution or emulsion can be administered to the 2-one according tothe following equation: mammal by injection. If desired the compoundcould also CH3 CH3 OH The starting material 4-methylene-5-methyl-5-ethy1be used in solid form mixed with a suitable diluent in a dioxolan-2-oneis a known material which is readily prep or table} calCfllm carbonate ala t se 0r mllk pared by reacting a tertiary acetylenic alcohol whosehy- Sugar are Sultable dlhlents for maklhg P the SOhd form foradministration. i y group 18 adjacent to mp 16 bond wlth carbon In orderto test the compound for its muscle relaxing dloxlde under pressfre andm h prfisence of copper and tranquilizing effect on warm-bloodedmammals, Compounds and ammes as descnbed 8 several difierent aqueoussolutions of the compound were ,2 The other Starting material,ethanolamme: prepared and administered intraperitoneally to the mice isreadily available mat al a to be tested. The results of the tests andthe different The following example will illustrate the preparationcompositions employed are shown in the following table.

Dose 750 mgJkg. 750 rug/kg. 1,500 mg/kg. 1,500 rug/kg. 1,500 rug/kg.6,000 mg./kg. 6,000 mg./kg.

Test interval, min -60 10-60 10-60 10-60 10-60 10-00 10-60.

' Present Present Present Present Present Present Present.

Normal Normal Normal orrnal Slight decrease..- Slight decrease.

do .do Slight decrease Slight decrease do Decreases.

Slight Absen Absent Absent Absent- Absent.

Sensitivity to handli Increase Normal Decreased Decreased DecreasedCompletely HlSellSl 1V0.

Passivity Not passive Not passive Slightly passive- Slightly passive-Slightly passive- Slightly passive- Completely DESSIVB- FearlulnessPresent Present Absent Absent Absent Absent Absent.

Muscle tone Normal Slightly flaccid Slightly llaeeid.. Flaceid FlaeeidVery flaccid--." Flaecid.

Palrebral opening "do". Normal. Droopy Droopy Droopy Droopy Droopy.

Respiratory rate do do Slew S1 Slow Slow.

Startle response Present P1esent Absent Absent Absent Absent Bodyposition. Normal Normal.-- t t t. Limb position do .do Close to body...Close to body-.. Close to body-.. Close to body Close to body.

It can be clearly seen from the test results that the aqueous solutionscan be easily and accurately prepared compound produces a tranquilizingeffect in warm-blooded for use and this is the preferred mode foradministering mammals as well as a strong muscle relaxing effect. thecompositions. Despite the soft muscle tone of some of the test mice,Iclaim: those at lower doses were able to coordinate, and could 1. Acomposition for producing muscle relaxation and hold on repeatedly iftested. Also, where the mice were a state of tranquility in awarm-blooded mammal comin an excited state before administration of thetest comprising a pharmaceutically acceptable carrier and an positionsafter administration they were totally indifferent effective amount ofthe compound 4,5-dimethyl-5-ethylto disturbance and in fact seemed toenjoy being handled. 4-hydroxy-3-hydroxyethyl-1,3-oxazolidin-2-one.

In over all effect the compound appeared to produce a 2. A method forproducing muscle relaxatlon and a dont-care reaction in the test mice.state of tranquility in a warm-blooded mammal com- The effective amountof 4,S-dimethyl-S-ethyl-4-hyprising administering to said warm-bloodedmammal an dr Xy-3hy r xy y -1, X n2- n o be m neffective amount of4,S-dimethyl-S-ethyl-4-hydroxy-3-hyistered to a warm-blooded animal toproduce muscle redroxyethyl-l,3-oxazolidin-2-0nc. laxation and a stateof tranquility is dose-dependent. Since the compositions are essentiallynontoxic, large amounts References Cited of the compounds can be safelyadministered. Doses of UNITED STATES PATENTS the compound ranglng from afew hundred mg./kg. to 2,575,694 11/1951 Spielman several thousandmg./kg. can be used with more of the dilute composition being added ifnecessary to increase STANLEY J FRIEDMANPrimary Examiner the amount ofmuscle relaxation and tranquilization. The

manner of administering the compositions is not critical, US. Cl. X.R.

and since water is an excellent solvent for the compound, 260307 .3

UNITED STATES PATENT} OFFICE CERTIFICATE OF CORRECTION Patent No. 3,5 ,9Dated November 2a, 1970 Inventor(s) Julius George Shukys It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 1, line 3'7, -3hydroxy" should read l-hydroxy.

Signed and sealed this 18th day of May 1971.

(SEAL) Attest EDWARD M.FLETCHER, JR. WILLIAM E. SCHUYLER, JR. AttestingOfficer Commissioner of Patents FORM PO1050[IO69) h n n A n

